title: Axonal neuregulin 1 is a rate limiting but not essential factor for nerve remyelination.
abstract: Neuregulin 1 acts as an axonal signal that regulates multiple aspects of Schwann cell development including the survival and migration of Schwann cell precursors, the ensheathment of axons and subsequent elaboration of the myelin sheath. To examine the role of this factor in remyelination and repair following nerve injury, we ablated neuregulin 1 in the adult nervous system using a tamoxifen inducible Cre recombinase transgenic mouse system. The loss of neuregulin 1 impaired remyelination after nerve crush, but did not affect Schwann cell proliferation associated with Wallerian degeneration or axon regeneration or the clearance of myelin debris by macrophages. Myelination changes were most marked at 10 days after injury but still apparent at 2 months post-crush. Transcriptional analysis demonstrated reduced expression of myelin-related genes during nerve repair in animals lacking neuregulin 1. We also studied repair over a prolonged time course in a more severe injury model, sciatic nerve transection and reanastamosis. In the neuregulin 1 mutant mice, remyelination was again impaired 2 months after nerve transection and reanastamosis. However, by 3 months post-injury axons lacking neuregulin 1 were effectively remyelinated and virtually indistinguishable from control. Neuregulin 1 signalling is therefore an important factor in nerve repair regulating the rate of remyelination and functional recovery at early phases following injury. In contrast to development, however, the determination of myelination fate following nerve injury is not dependent on axonal neuregulin 1 expression. In the early phase following injury, axonal neuregulin 1 therefore promotes nerve repair, but at late stages other signalling pathways appear to compensate.
authors.affiliation: The Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU UK.
authors.forename: Florence R
authors.initials: FR
authors.lastname: Fricker
authors.forename: Ana
authors.initials: A
authors.lastname: Antunes-Martins
authors.forename: Jorge
authors.initials: J
authors.lastname: Galino
authors.forename: Remi
authors.initials: R
authors.lastname: Paramsothy
authors.forename: Federica
authors.initials: F
authors.lastname: La Russa
authors.forename: James
authors.initials: J
authors.lastname: Perkins
authors.forename: Rebecca
authors.initials: R
authors.lastname: Goldberg
authors.forename: Jack
authors.initials: J
authors.lastname: Brelstaff
authors.forename: Ning
authors.initials: N
authors.lastname: Zhu
authors.forename: Stephen B
authors.initials: SB
authors.lastname: McMahon
authors.forename: Christine
authors.initials: C
authors.lastname: Orengo
authors.forename: Alistair N
authors.initials: AN
authors.lastname: Garratt
authors.forename: Carmen
authors.initials: C
authors.lastname: Birchmeier
authors.forename: David L H
authors.initials: DL
authors.lastname: Bennett
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009154:Mutation / Q000235:genetics; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism*; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000235:genetics; D009416:Nerve Regeneration / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D059348:Peripheral Nerve Injuries / Q000473:pathology / Q000503:physiopathology*; D011506:Proteins / Q000235:genetics; D022661:RNA, Untranslated; D020127:Recovery of Function / Q000235:genetics; D012018:Reflex / Q000187:drug effects / Q000235:genetics; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D013116:Spinal Cord / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D013997:Time Factors
chemical_list: C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D009185:Myelin Proteins; D062559:NAV1.8 Voltage-Gated Sodium Channel; D020890:Neuregulin-1; D011506:Proteins; D022661:RNA, Untranslated; C568318:Scn10a protein, mouse; D013629:Tamoxifen; D001973:Bromodeoxyuridine
keywords: Nrg1; Schwann; injury; regeneration; remyelination